Effects Of Genomic Copy Number Variation On Gender Disparity In Hepatocellular Carcinoma And Its Related Mechanisms

Hepatocellular carcinoma(HCC) is one of the most common and fatal human cancers with significant gender disparity. Regardless of etiologies, males are about two to four times more likely to develop HCC than females. However, the reason of gender disparity in HCC was not well defined, especially from the genomic alterations. For the gender disparity, previous studies have confirmed the crucial roles of cytokines, especially IL-6. In mice models, serum IL-6 concentration can be reduced by estrogens at a Myd88-dependent manner to inhibit the diethylnitrosamine(DEN)-induced hepatocarcinogenesis. In human, serum IL-6 was an independent risk predictor for HCV-related HCC development in females. For the underlying mechanisms, some studies had well defined the important mediators of IL-6 in HCC, however, just under short-term IL-6 stimulation. Alfred et. had showed a different role of IL-6 under long-term stimulation from short-term stimulation in prostate cancer. So the role and exact underlying mechanism of HCC onset under continuous IL-6 microenvironment need more studies.Copy number variations(CNVs), as one of the important components of genomic variations in human, are closely associated with many genetic and developmental disorders. Differently expressed tumor suppressor genes and oncogenes due to the CNVs were regarded as the crucial cause of many types of cancer, including HCC. However, whether gender disparity of CNVs in HCC exists, what induces the formation of gender disparity in CNVs, and how the gender associated CNVs affect the HCC genesis and progress were all unclear.To explore exact mechanisms of gender disparity in HCC carcinogenesis, reanalysis of large-scale genomic profiles from published data was performed to identify candidate genomic alterations with gender disparity, and the gender differences in genomic and transcriptional levels were further confirmed in an independent HCC Cohort. Using hepatic cell lines and HCC cell lines, we explored the role of key gene with gender disparity in copy number variations in HCC carcinogenesis and the driving mechanisms for the conformation of gender bias. Large-scale genomic analyses confirmed the gender disparity in genomic alterations in HCC and suggested the CNVs of UBE2D1 as the key event associated with gender disparity. UBE2D1 can facilitate the HCC growth by activating the p53 ubiquitination and was correlated with reduced survival of HCC patients. Additionally, the gender disparity of CNVs in HCC was ascribed to the continuous IL-6 microenvironment. Continuous IL-6 stimulation promoted the replication stress responseand genomic instability to drive the genomic amplification of UBE2D1 by activating STAT3 and thus repressing RAD51 B. Moreover, continuous IL-6 can significantly facilitate the HCC growth and carcinogenesis especially when the CNVs of UBE2D1 occur.Conclusion: Our findings clarified the mechanisms of gender disparity in CNVs and suggested UBE2D1 and RAD51 B as potential therapeutic targets for HCC. Significance: Large-scale genomic analyses confirmed the gender disparity in genomic alterations in HCC and suggested the CNVs of UBE2D1 as the key event associated with gender disparity. UBE2D1 promoted HCC growth in vitro and in vivo and was correlated with reduced survival of HCC patients. Continuous IL-6 stimulation initiated and maintained the replication stress response by activating the autocrine loop, resulting in accumulated genomic instability and CNVs formation, which may be responsible for the unsatisfied benefits of sex hormones drugs to repress IL-6. Continuous IL-6 can significantly facilitate the HCC growth and carcinogenesis especially when the CNVs of UBE2D1 occur. Our study suggested that pathways in continuous IL-6 may serve as the potential targets in sex hormones targeted therapy.